Fatty acid amide hydrolase (FAAH) is known to hydrolyze endocannabinoid to inactivate it (see Non-Patent References 1 to 4). Endocannabinoid is a generic term for a biological substance that acts on a cannabinoid receptor to exhibit its physiological activity. Typical endocannabinoids are anandamide, palmitoyl ethanolamide, oleamide, 2-arachidonoyl glycerol; and they are known to be hydrolyzed by FAAH to lose their activity. Δ9-tetrahydrocannabinol that is considered as the active ingredient of Cannabis (marijuana) is known to activate a cannabinoid receptor (see Non-Patent Reference 5).
In mammals, two types of cannabinoid receptor CB1 and CB2 have heretofore been known. CB1 is expressed in central and peripheral nervous systems, and when activated, it exhibits its mental action and analgesic action. CB2 is expressed in immune systems, and when activated, it exhibits its antiinflammatory action and analgesic (and antiinflammatory) action.
On the other hand, in a cystitic rat model, a cannabinoid receptor agonist increases the bladder capacity and the urination threshold (Non-Patent Reference 6 and Non-Patent Reference 7); and the side effects of hallucination, delusion, tachycardia, orthostatic hypotension to be observed in administration of a cannabinoid receptor agonist to animals are not observed when an FAAH inhibitor is administered thereto (Non-Patent Reference 8). From these, the FAAH inhibitor is expected as a remedy for urinary frequency and urinary incontinence, a remedy for overactive bladder and/or a remedy for pain.
As compounds having an FAAH-inhibitory activity, known are compounds capable of serving as analgesic, antianxiety, antiepileptic, antidepressant, antiemetic, cardiovascular agent or antiglaucomatous agent [C1-4 alkyl or polycyclic aromatic ester derivatives of aromatic ring or phenyl-substituted aliphatic hydrocarbon-carbamic acids (Patent Reference 1) and phenyl cyclohexylcarbamate (Patent Reference 2)]. Dioxane-2-alkylcarbamate derivatives, which are compounds having an FAAH-inhibitory activity, are described as a remedy for urinary incontinence, one embodiment of a large number of disorders listed therein (Patent Reference 3). However, Patent Reference 3 does not disclose experimental results to support the remedial effect for treatment of urinary frequency and urinary incontinence and/or for treatment of overactive bladder, not disclosing any suggestion for it. 4-Aminopyridyl piperidine-1-carboxylate, a type of pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylates, is described as an acetylcholine esterase inhibitor (Non-Patent Reference 9); however, the reference describes nothing about the compound to be a remedy for urinary frequency and urinary incontinence and/or a remedy for overactive bladder.
Patent Reference 1: WO2003/065989
Patent Reference 2: WO2004/033422
Patent Reference 3: JP-A 2003-192659
Non-Patent Reference 1: Prostaglandins Leukotrienes and Essential Fatty Acids, (England), 2002, Vol. 66, pp. 143-160
Non-Patent Reference 2: British Journal of Pharmacology (England), 2004, Vol. 141, pp. 253-262
Non-Patent Reference 3: Nature (England), 1996, Vol. 384, pp. 83-87
Non-Patent Reference 4: Biochemical Pharmacology, (USA), 2001, Vol. 62, pp. 517-526
Non-Patent Reference 5: Current Medicinal Chemistry (USA), 1999, Vol. 6, pp. 635-664
Non-Patent Reference 6: The Journal of Neuroscience, 2002, Vol. 22, pp. 7147-7153
Non-Patent Reference 7: Pain, 1998, Vol. 76, pp. 189-199
Non-Patent Reference 8: Nature Medicine, (England), 2003, Vol. 9, pp. 76-81
Non-Patent Reference 9: Journal of Pharmaceutical Science, 1992, Vol. 81, pp. 380-385